ES2841940T3 - Complexes and compositions for the treatment of ophthalmic and dermatological diseases - Google Patents

Abstract

A topical composition comprising - a component with miticidal and biocidal activity - a physiologically acceptable crosslinked polymer and a dermatologically acceptable carrier, characterized in that the miticidal and biocidal component is terpinen-4-ol and the crosslinked polymer is hyaluronic acid crosslinked with urea.

Description

DESCRIPTION

Complexes and compositions for the treatment of ophthalmic and dermatological diseases

The present invention relates to a complex and compositions for the treatment of ophthalmic and dermatological diseases.

Specifically, the present invention relates to a cross-linked hyaluronic acid-based complex for the treatment or prevention of ophthalmic or dermatological diseases, also caused by mite infestations. The compositions of the invention find application in the cosmetic, dermatological and ophthalmic fields. State of the art

Blepharitis is an inflammatory process of the free edge of the eyelid that can spread to the skin, conjunctiva, follicles, ciliary glands, and meibomian glands. Blepharitis can have subacute or chronic evolution, with resistance to therapeutic treatments and a tendency to relapse. The main symptoms of blepharitis are heartburn, itching, tearing, a feeling of heat or weight, photophobia, and blepharospasm.

The flaking, in addition to eye irritation and slight blemishes, triggers a vicious cycle that fuels blepharitis. The presence of external agents at the lid margin creates a physical barrier for the physiological drainage of the glandular ducts, obstructing them and creating environmental conditions conducive to the formation of bacterial colonies.

The etiology of blepharitis is multiple. Blepharitis can be caused by constitutional, allergic, endocrine environmental factors, such as dust and smoke, by avitaminosis, dyspepsia, food autointoxication, diabetes, or by microorganisms, usually staphylococci or mites.

A common concause of blepharitis is represented by an infestation of the periocular and pilosebaceous area by Demodex folliculorum, an ectoparasite belonging to the class of Arachnida, subclass Acarina.

This mite feeds on the secretions of fat cells and, by infesting the follicles of the eyelashes, it can also cause them to fall.

Although there are many species of this mite, only Demodex brevis and Demodex folliculorum can infest humans.

Demodex infestation is quite widespread and is usually contracted as a result of direct contact with the skin of an infested individual or from the dust contained in their eggs.

A study by Junemann A., titled Demodex folliculorum in chronic blepharitis, revealed that Demodex folliculorum infestation is present in approximately 25% of 20-year-olds, 30% of 50-year-olds, and 100% of patients over 90 years old.

It has also been found that, at intervals of about ten tabs, one or more Demodex mites can nest even in asymptomatic healthy patients.

Demodex folliculorum generally forms colonies, within the hair follicles and on the eyelashes. The presence of D. folliculorum is often associated with anterior blepharitis.

The main symptoms attributable to Demodex folliculorum infestation include redness of the eyelids, a foreign body sensation, itching of the eyelids and eyebrows, madarosis, and a burning sensation.

Infestation by D. folliculorum has also been observed to cause follicular hyperplasia, resulting in increased keratinization near the base of the eyelid. Additionally, Demodex- infested lashes are often brittle and easily lost.

Infestation by another species of mite, such as Demodex brevis, which generally lives in the oil glands of the skin and eyelids, has also been found to contribute to the development of blepharitis.

The prevention of blepharitis is carried out by careful hygiene of the eyelids, which involves the elimination of external agents, and make-up, secretions and sebum from the eyelashes and the periocular area.

However, in many cases, blepharitis is not completely eradicable. Also, if not treated properly, it can lead to complications such as stye formation, chalazion, loss of eyelashes, and recurrent conjunctivitis.

Treatment of blepharitis, particularly of the infectious and ulcerative forms, is based on the application of topical products, such as ointments, creams, and ointments containing antibiotics, possibly in combination with corticosteroids.

The treatments currently available on the market have not been entirely effective, as they cannot completely eradicate the infestation and, in some cases, lead to the formation of bacterial colonies that develop resistance to the applied antibiotics.

Also known from US Patent No. 8,455,015B2A is a composition for the treatment of Demodex infestations, which contains as an active ingredient tea tree oil (TTO), an essential oil derived from Melaleuca alternifolia, a native plant from eastern Australia, belonging to the Myrtaceae family.

TTO consists of a mixture of about one hundred substances that include terpenic hydrocarbons, mainly monoterpenes, sesquiterpenes and their alcohols, obtained by steam distillation of Melaleuca alternifolia leaves. Of the components present in the plant extract, seven were found to have broad-spectrum anti-inflammatory or antibacterial activity. S. Tighe et al. "Terpinen-4-ol is the Most Active Ingredient of Tea Tree Oil to Kill Demodex Mites", Trans. Vision Science & Technology 2013, vol. 2, n ° 7, page 2 describes that terpinen-4-ol is the most active ingredient in TTO to exert antibacterial and antifungal effects.

WO 2009/018060 A1 describes an aqueous ophthalmic composition comprising a natural polymer selected from hyaluronic acid and a terpene compound such as 1-terpinen-4-ol. EP 1444 984 A1 describes a topical pharmaceutical composition comprising hyaluronic acid and Melaleuca alternifolia extracts. "Blephapad" (http://www.italianinnovation.net/upload/img/75db686b-c6fb-484c-a8e2-35f720f78b92.pdf, 05-09-2016) describes pads comprising hyaluronic acid and 1-terpinen-4-ol (as a complex) for the treatment of eyelid disorders.

The Brand C publication, Grimbaldeston MA, Gamble JR, Drew J, Finlay-Jones JJ, Hart PH. "Tea tree oil reduces the swelling associated with the efferent phase of a contact hypersensivity response"; Inflamm Res 2002; 51: 236-44 reports the anti-inflammatory activity of TTO.

The publications of Dryden MS, Dailly S, Crouch M. "A randomized, controlled trial of tea tree topical preparations versus a standard topical regimen for the clearance of MRSA colonization"; J Hosp Infect 2004; 56: 283-6, and by Kwiecinski J, Eick S, Wojcik K. Effects of tea tree ( Melaleuca alternifolia) oil on Staphylococcus aureus in biofilms and stationary growth phase; Int J Antimicrob Agents 2009; 33: 343-7 report on the antibacterial action of TTO against microorganisms, including germs commonly isolated from the oral cavity of cancer patients, such as Staphylococcus aureus, including MRSA (methicillin-resistant Staphylococcus aureus).

The publication of Jobbins J, Bagg J, Parsons K, Finlay I, Addy M, R.G. Newcombe "Oral carriage of yeasts, coliforms and staphylococci in patients with advanced malignant disease" in J. Oral Pathol Med 1992; 2; 21 (7): 305-8 reports the action of TTO against coliform bacterial infections.

The use of TTO in the treatment of the Herpes simplex virus, the reactivations of which constitute a more serious clinical problem for terminally ill patients, is also known by Carson CF, Ashton L, Dry L, Smith DW, Riley TV in "Melaleuca alternifolia (tea tree) oil gel (6%) for the treatment of recurrent herpes labialis ", J Antimicrob Chemother 2001; 48: 450-1.

TTO, although considered a safe product for external applications, can cause allergic reactions, as documented by Veien NK, Rosner K, Skovgaard GL (2004) "Is tea tree oil an important contact allergen?" Contact Dermatitis 50: 378-379, or skin irritation and rashes, burning, itching, or contact dermatitis.

TTO, in pure or diluted form, has also been found to be irritating to mucous membranes, especially the mucous membrane of the eye, as documented in Southwell IA, Freeman S, Rubel D (1997), "Skin irritancy of tea tree oil ", J Essent Oil Res 9: 47-52).

Therefore, TTO has a number of limitations for local application to sensitive areas of the skin, such as the periocular area.

Furthermore, the external use of the active components of TTO is limited due to its strong organoleptic component. In international application WO 2015/007773 A1 issued to I.R.A. S.r.l., the inventors Dr. Citernesi et al. describe the preparation of a biocompatible cross-linked biopolymer comprising urea-cross-linked hyaluronic acid and its applications. Therefore, at present there is a need for products and compositions for ophthalmic and / or dermatological use that have a disinfecting effect against mites and other microorganisms that infest the skin.

One of the objectives of the invention is to test a product or a composition that is applicable in the prevention and treatment of blepharitis and / or infestation by mites, in particular Demodex.

Another objective is to provide an ophthalmic composition for the treatment of infections of bacterial origin and / or infestations of mites in the periocular area, the use of which implies a reduced risk of triggering local allergic reactions, or inflammation, or irritation of the treated skin areas. .

Another object of the invention is to provide a topical or ophthalmic composition for the treatment of blepharitis or mite infections, which does not have an intense, persistent and annoying odor perceived by the subject in need of treatment.

Summary

The inventors have discovered that the combination of a selected TTO component, provided with antibacterial and miticidal activity, with a cross-linked polymer compatible with the skin, results in an effective treatment of blepharitis and / or mite infestation, in particular by Demodex , in the substantial absence of local adverse reactions.

It has also been surprisingly discovered that by complexing terpinen-4-ol, an active component of TTO, with a cross-linked polymer based on hyaluronic acid, the organoleptic appearance of the acaricidal component is greatly improved.

According to a first aspect, the present invention therefore provides a topical composition, especially for the prevention and / or treatment of ophthalmic and / or dermatological diseases, comprising - a component with acaricidal and / or biocidal activity

- a physiologically acceptable cross-linked polymer and a dermatologically acceptable carrier, characterized in that the acaricidal component is terpinen-4-ol, and the cross-linked polymer is cross-linked hyaluronic acid. Further embodiments of the composition of the invention are defined in the appended claims 2 to 5.

According to certain aspects, in the composition of the invention the cross-linked hyaluronic acid and the terpinen-4-ol form a complex.

Therefore, a further object of the present invention is a complex based on hyaluronic acid cross-linked with urea and terpinen-4-ol.

Therefore, the complex according to this aspect of the invention comprises two components:

a) terpinen-4-ol, and b) a hyaluronic acid-based cross-linked polymer cross-linked with a cross-linking agent. A suitable crosslinking agent is selected from water soluble carbodiimides, divinyl sulfone, 1,4-butanediol diglycidyl ether, crosslinking agents containing multiple amino groups and urea.

According to some preferred embodiments, the cross-linked polymer of the complex of the invention is hyaluronic acid cross-linked with urea.

Typically, the complex of the invention is a biocompatible and / or physiologically acceptable cross-linked macromolecular matrix.

According to another aspect, the present invention provides a composition for the prevention and / or treatment of blepharitis and / or skin mite infestations, comprising terpinen-4-ol and a physiologically acceptable cross-linked polymer based on cross-linked hyaluronic acid, For use in treating blepharitis, mite infestations, acne, rosacea.

The composition of the invention finds a specific application in the treatment of Demodex infestations and Demodex- induced blepharitis .

Typically, the composition of the invention is used for external use, specifically for application to the skin, for example in the periocular area and all the appendages of the eye.

Brief description of the figures

The present invention will be described in detail below, and with reference to the figures, in which:

Figure 1 shows a photographic reproduction of a 20x resolution microscopic view of Dermatophagoides pteronyssinus in a Petri dish treated according to Example 5 of the description;

Figure 2 shows a further photographic reproduction of a 40x resolution microscopic view of Dermatophagoides pteronyssinus in a Petri dish treated according to Example 5 of the disclosure; Figure 3 shows bar graphs related to benchmarking tests of tolerability and organoleptic characteristics in the use of wipes soaked with tea tree oil (TTO), terpinen-4-ol (T4O) and cross-linked hyaluronic acid / terpinen-4. -ol (Hy-Ter) of the invention.

Detailed description of the invention

According to a first aspect of the invention, there is provided a topical composition as defined in claim 1 attached hereto.

According to another aspect, the invention relates to a complex of terpinen-4-ol with a polymer of hyaluronic acid cross-linked with a physiologically or cosmetically acceptable cross-linking agent.

One of the advantages of the composition and complex of the invention resides in being substantially free of the pungent and persistent odor typical of preparations containing tea tree oil (TTO), or extracts thereof.

Terpinen-4-ol from the Complex

One of the components of the composition and the complex of the invention is terpinen-4-ol, a monoterpenic alcohol with the IUPAC name of 1-isopropyl-4-methyl-3-cyclohexen-1-ol.

The terpinen-4-ol of the complex of the invention can be of synthetic or natural origin. For example, it can be obtained by extracting the TTO obtained from the leaves of the tea tree. In accordance with some aspects of the invention, Applicant has discovered that by complexing a selected monoterpenic alcohol with a cross-linked hyaluronic acid-based polymer, a product with improved compatibility is obtained.

Complex Cross-linked Hyaluronic Acid

Another component of the composition and complex of the invention is a cross-linked hyaluronic acid-based polymer.

Typically, the hyaluronic acid-based polymer can be cross-linked with a cross-linking agent selected from urea, water-soluble carbodiimides, divinyl sulfone, 1,4-butanediol diglycidyl ether, or cross-linking agents containing multiple amino groups.

According to a preferred embodiment, the cross-linked hyaluronic acid of the complex of the invention is cross-linked with urea.

Realization with Hyaluronic Acid Crosslinked with Urea

In some embodiments, the polymeric component of the hyaluronic acid-based complex crosslinked with urea and terpinen-4-ol has a molecular weight ranging from 100,000 to 20,000,000 daltons, 500,000 to 10,000,000 daltons, 1,000,000 to 6,000 .000 daltons, typically 2,000,000 to 4,000,000 daltons, preferably 1,500,000 to 1,800,000 daltons.

Typically, the hyaluronic acid of the cross-linked polymeric component of the complex is a polysaccharide, made up of alternating units of glucuronic acid and N-acetylglucosamine, capable of retaining water and resisting hydrostatic stresses.

Typically, the molecular weight of the polymers described herein, such as hyaluronic acid, is a weight average molecular weight (Mw) that can preferably be determined with the SEC-MALLS technique or laser light scattering size exclusion chromatography of multiple angles.

In some embodiments, in the complex of the invention, the urea cross-linked hyaluronic acid can be prepared separately by cross-linking hyaluronic acid, or a salt thereof, with urea, typically in an acidic environment. For example, hyaluronic acid, or its salts, and urea can be dissolved and / or combined in a liquid, for example water, in which both components are soluble. In some embodiments, hyaluronic acid in aqueous solution is present in an amount ranging from 2 mg / ml to 120 mg / ml, 5 to 25 mg / ml, typically 7 to 20 mg / ml. According to some embodiments, urea in acidic aqueous solution is present in a concentration ranging from 1 to 100 mg / ml, 3 to 50 mg / ml, typically 5 to 25 mg / ml.

According to some embodiments, the weight ratio of hyaluronic acid, or a salt thereof, and urea in the aqueous solution or crosslinking reaction mixture can range from 0.3 to 10, from 0.8 to 5, from 1 to 3.

In some embodiments, the obtained mixture has a pH ranging from 3.5 to 4. In some embodiments, an acid such as HCl is added to obtain the acidic pH of the solution.

Optionally, in case the mixture has a pH outside 3.5-4, it is possible to add a pH correcting agent, such as a solution of an acid, for example HCl, or a base, for example NaOH.

In some embodiments, to adjust the pH in the range 3.5-4, a buffer such as, for example, acetic acid and sodium acetate can be added.

In some embodiments, the mixture is thermostatted, for example, at 35 (+/- 2) ° C, for 20-24 hours, and then expanded to remove excess urea present in the solution.

According to some embodiments, the pH of the obtained product varies between 5.5 and 7.5. If the pH deviates from the 5.5 to 7.5 range, it can be adjusted by adding a 0.2 M NaOH solution, in one or more portions, until it is within the desired range.

In certain embodiments, at the end of the cross-linking reaction, the obtained biocompatible cross-linked polymer is reduced to particles or homogenized through a sieve having a pore size of, for example, between 5 and 150 microns, conveniently 40 to 80 microns, to form a hydrogel.

Completions of the Complex

According to some embodiments, the complex has a content of terpinen-4-ol ranging from 0.1 to 25% by weight, based on the total weight of the complex, from 1 to 20% by weight, from 3 to 18%. by weight, 5% to 15% by weight. Typically, the complex of the invention comprises an active component, represented by terpinen-4-ol, which is released from the cross-linked hyaluronic acid-based complex component.

According to some embodiments, the complex of the invention is in the form of a hydrogel and is preferably a complex of terpinen-4-ol and hyaluronic acid cross-linked with urea (Examples 1 and 2).

In some embodiments, the complex of the invention is provided in sterile form, suitable for medical or cosmetic applications.

Complex Preparation Method

In accordance with certain aspects, the present invention provides a method for preparing the complex of the invention according to a previously defined embodiment.

Typically, the preparation method of the invention comprises crosslinking hyaluronic acid, or a salt thereof, with a crosslinking agent of the type previously described, preferably urea, in the presence of terpinen-4-ol, preferably in an acidic environment.

According to some embodiments, the method of preparing a urea-terpinen-4-ol cross-linked hyaluronic acid complex comprises mixing a terpinen-4-ol solution with a hyaluronic acid solution, or a salt thereof, adding a urea solution and mixing, preferably maintaining the mixture at a pH of 3.5 to 4. According to some embodiments, the product resulting from the previous step is brought to temperatures above room temperature, for example in the range of 30 to 40 ° C, for a period of time suitable to form the complex, for example 20-24 hours. In some embodiments, the resulting mixture is purified from excess urea to a pH in the range of 5.2 to 7.2.

By way of example, the complex consisting of urea crosslinked hyaluronic acid and terpinen-4-ol can be prepared as follows.

Sodium hyaluronate is dissolved in an aqueous solution of sodium chloride.

Separately, the terpinen-4-ol is dissolved in a solution of polysorbate 20 and pentylene glycol.

Separately, urea is dissolved in a 0.2 M HCl solution.

The terpinen-4-ol solution is progressively added to the sodium hyaluronate solution kept under continuous stirring. Stirring is continued until a homogeneous mixture is obtained.

The urea solution is progressively added to the latter solution, maintained under vigorous stirring by means of a turboemulsifier.

The pH is measured and should be within the range of 3.5 to 4.0; otherwise, it is set to this value.

The product is thermostatted at 35 ° C ± 2 ° C for 20-24 hours, then purified with any excess urea until the pH is within the range of 5.2-7.2.

Definitions

Within the scope of the invention, the term "hyaluronic acid salt" is intended to include hyaluronic acid (free form) and any water soluble salt of hyaluronic acid, such as sodium, potassium or calcium salt.

Within the scope of the invention, the term "biopolymer" or "polymer" are equivalent, and both designate a polymer that is physiologically, dermatologically or cosmetically acceptable, that is, compatible with the epidermis of the human body.

The term "dermatologically acceptable" refers to vehicles or excipients that do not substantially cause any skin irritation, inflammation or damage when applied thereto.

The term "ophthalmically acceptable" refers to non-detergent vehicles or excipients that do not irritate or substantially damage the surface of the eye and its appendages, such as eyelashes and eyebrows.

Within the scope of the present invention, the term "carrier" refers to an excipient or diluent that does not have pharmacological activity, and may be present in the composition of the invention, for example, as a carrier element.

The term "complex" designates a product based on / comprising hyaluronic acid cross-linked with urea and terpinen-4-ol, in which the hyaluronic acid cross-linked with urea is linked by secondary bonds and / or by weak molecular interactions with terpinen-4 -ol.

Compositions Containing the Complex

According to one aspect, the present invention provides a composition comprising a complex based on cross-linked hyaluronic acid and terpinen-4-ol according to any one of the embodiments described above, and a physiologically acceptable carrier.

According to a preferred embodiment, the composition of the invention comprises a complex based on hyaluronic acid cross-linked with urea and terpinen-4-ol.

The composition of the invention is in a form suitable for topical application.

Typically, the active component of the composition of the invention is represented by cross-linked hyaluronic acid and the terpinen-4-ol complex. As we have seen, terpinen-4-ol is released into the environment by the cross-linked hyaluronic acid complex component.

Typically, the physiologically acceptable carrier of the composition is a dermatologically acceptable and / or ophthalmically acceptable carrier.

According to certain embodiments, the composition of the invention contains a dermatologically acceptable and / or ophthalmically acceptable excipient or vehicle, and an amount of any embodiment of the complex in an amount ranging from 0.1 to 20% by weight, from 0, 5 to 15%, 1 to 10% by weight.

Formulations suitable for topical application include solutions, suspensions, lotions, creams, gels, ointments, pastes, salves, microemulsions, sprays, drops, foams, shampoos, roll-ons, substrates or devices to support the components of the composition, preferably wipes.

In some embodiments, the compositions of the invention may comprise excipients commonly used in the formulation of dermatological, cosmetic, or pharmaceutical preparations for topical use, such as preservatives, bactericidal agents, stabilizers, emulsifiers, buffers, wetting agents, dyes, and other commonly used excipients. in cosmetic / pharmaceutical preparation techniques.

According to some embodiments of the invention, there is provided a device for the hygienic and / or disinfecting treatment of the periocular area comprising a substrate and a composition according to any one of the embodiments described above.

According to certain embodiments, the substrate is a fabric, for example hydrophilic cotton, or a non-woven fabric, for example polyester, or a polyurethane-based backing.

In some embodiments, the device is a wipe, gauze, or wipe suitable for application to the ocular and / or periocular area.

In some embodiments, the device according to any one of the embodiments described above is moistened or soaked with a composition according to any one of the preceding embodiments. According to some embodiments, the device of the invention is moistened with an amount of composition of 0.001 to 0.1 g / cm2.

Typically, the device moistened with the composition is packaged in a hermetically sealed container, such as an aluminum foil bag or envelope.

In some forms for applications of the device in the medical or ophthalmic field, the device is in sterile form and / or vacuum packed. Sterilization can be carried out according to conventional procedures in pharmaceutical technology, for example by exposure to an atmosphere of ethylene oxide or gamma rays. According to some embodiments, the device is a medical device.

Cosmetic and Medical Uses of Complexes / Compositions

In the medical field, the complex of the invention and the compositions containing it find application in the treatment of diseases that include infestations of mites, in particular infestation by Demodex, by Cheyletiella mite, or by bacteria, as in the following non-exhaustive examples : blepharitis, acne, rosacea, acute or chronic conjunctivitis, conjunctivitis with an allergic component. In general, the composition of the invention can be used for the treatment and control of infestations by any species of Demodex.

The composition of the invention finds specific use in the treatment of Demodex infestations and / or Demodex- induced blepharitis, and to prevent or delay relapses.

According to some embodiments, the complex and composition of the invention are used in the treatment of bacterial infections of the eye and / or skin, in particular Staphylococcus. In particular, the composition of the invention finds application in the treatment of blepharitis and / or rosacea.

In the cosmetic field, the complex or composition of the invention finds application in the detersion or hygiene of the periocular area, eyelid and / or eyelashes. The composition of the invention can be applied or rubbed on eyelashes, eyelids or periocular areas to clean or disinfect the contact area in order to eliminate contamination from external agents and / or mites.

In the embodiments of the device in the form of a gauze or wipe, it is convenient to apply them on the surface of the eyelid, keeping the eye closed, possibly by means of circular movements that allow deep cleaning of the treated areas, and eliminate the impurities present on the epithelium, keeping a natural hydration of the skin, and underneath.

In the medical and ophthalmic field, the use of the device in the ocular or periocular area sanitizes the treated area by reducing the bacterial load present. In addition, the germicidal action is combined with a soothing action that reduces redness due to the action of environmental agents and / or developed microorganisms.

According to some aspects, the device of the invention, in particular in the form of a gauze moistened with the composition, finds use in the medical field in the prevention and / or treatment of blepharitis, conjunctivitis, blepharoconjunctivitis or infections of the lacrimal sac.

The present invention will now be described with reference to the following examples, which are provided for illustrative purposes only and are not to be construed as limiting the scope of the present invention.

EXAMPLE 1

Composition for topical use in the form of wipes containing the complex of the invention

Hyaluronic acid complex cross-linked with urea and Terpinen-4-ol 5.0%

Aloe Barbadensis leaves, dry extract

PEG / PPG-20/15 Dimethicone

Ammonium glycyrrhizate

Capryl / Capryl glucoside

Sodium cocoil amino acids

Ethylhexylglycerin

Phenylethyl alcohol

Sodium chloride

Sodium phosphate

Disodium phosphate

PPG-26 Buthet-26

PEG-40 Hydrogenated Castor Oil

Water

Preparation method

The raw materials, previously dispensed from the weighing room, are combined in a reactor and mixed until a homogeneous solution is obtained.

The wipes are produced by a special machine that provides:

a) cut and form the gauze;

b) dosing the previously prepared solution;

c) inserting the soaked gauze into the mating material of the envelope;

d) heat seal the envelope on 4 sides;

e) etching a tear notch;

f) print variable data.

The sachets thus produced are packed in boxes together with the leaflet.

EXAMPLE 2

Composition for topical use in the form of a cream containing the complex of the invention.

Product composition:

Phase a

Polyglyceryl-3-diisostearate 4.50%

Polyglyceryl-6-dioleate 3.00%

Glyceryl Behenate 2.00%

Vegetable squalene 5.00%

Sweet almond oil 2.00%

Vaseline oil 10.00%

Tocopherol 0.03%

Phase b

Demineralized water 55.47%

Sodium chloride 0.50%

Magnesium sulfate 7 H2O 0.50%

Glycerin 7.00%

Phase C

Demineralized water 5.00%

Cross-linked hyaluronic acid complex / terpinen-4-ol 5.00%

EXAMPLE 3

Method for preparing the composition of Example 2

Heat Phase A to approximately 80 ° C until all components are completely melted. Heat Phase B to approximately 80 ° C.

While keeping Phase A under rapid agitation with a turbine shaker, slowly add Phase B. Continue agitating the turbine for approximately 15 minutes.

Cool with stirring to approximately 35 ° C, then add Phase C.

Complete cooling with gentle agitation.

EXAMPLE 4

Components for preparing a composition of the disclosure in which the sodium salt of hyaluronic acid (component 2) is cross-linked with component 3 and component 4 is a cross-linking agent:

1. Terpinen-4-ol 10.0%

2.Hyaluronic Acid Sodium Salt 3.0%

Urea 4,0%

Urea 4.0%

4. Pentylene glycol 5.0%

5. Sodium chloride 0.9%

Polisorbato 20 10,0%

Polysorbate 20 10.0%

Agua purificada c.s. hasta 100%

Purified water qs up to 100%

EXAMPLE 5

Activity of Wipes soaked with the Composition of the Invention on Mites

This experiment was carried out to verify the acaricidal activity of the key component of Melaleuca alternifolia conjugated with hyaluronic acid (Cross-linked hyaluronic acid-urea / terpinen-4-ol complex) in different doses (0.5%, 1% and 2% ) in dust mites Dermatophagoides pteronyssinus (DP). Negative controls (neutral wipes) and positive controls (Cliradex, an American product containing a high dose of Terpinen-4-ol) were also used in parallel, along with a commercial product containing phenylethyl alcohol, an organic component active against DP. D. pteronyssinus mites kept in the laboratory for more than 20 years without exposure to any known acaricide were used. The mites were reared in plastic containers (12.5 x 10.5 x 5.0 cm) at 25.0 ± 1.0 ° C, 75% relative humidity in a dark room and fed a diet patented.

Each of the wipes, formulated with different concentrations of hyaluronic acid / terpinen-4-ol complex or alcohol, was placed at the bottom of a Petri dish (5 cm diameter, 1.2 cm high). An amount of approximately 300 DPs was placed on the wipe in each of the Petri dishes, which were then closed with the lid. The movement of the body and legs of Dermatophagoides pteronyssinus (Figures 1 and 2) was continuously observed with a binocular microscope for up to 30 minutes.

The "100% mortality time (MT)" was defined as the time when all PD movements ceased. The acaricidal effect of Crosslinked Hyaluronic Acid / Terpinen-4-ol Complex is dose dependent, as shown in Table 1.

Table 1:

Conclusions

A clear dose dependence of the acaricidal effect of the cross-linked hyaluronic acid / Terpinen-4-ol complex against DP was highlighted.

EXAMPLE 6

In vivo Skin Tolerability of Composition-Soaked Wipes

An in vivo study was carried out in healthy volunteers to evaluate the subjective perception of using a wipe soaked with the same concentration (0.5%) of tea tree oil (TTO), Terpinen-4-ol (T4O) and a Cross-linked hyaluronic acid (urea) / Terpinen-4-ol complex.

The test was carried out in order to verify whether the cross-linked hyaluronic acid / terpinen-4-ol complex has comparable or better organoleptic characteristics than TTO or T4O.

For this, 15 healthy volunteers, aged 27 to 65, 9 women and 6 men, were treated with the wipes described above, blindly evaluating four variables: sensation of freshness around the eye area, perception of smell, absence of local irritation and tactile sensation, using a rating scale of 5 (5 = very pleasant, 4 = pleasant, 3 = neutral, 2 = unpleasant, 1 = very unpleasant).

The results are shown in the attached Figure 3.

Conclusions

The inclusion of Terpinen-4-ol in the cross-linked hyaluronic acid complex has improved the organoleptic characteristics of the product.

Claims (11)

1. A topical composition comprising - a component with miticidal and biocidal activity - a physiologically acceptable cross-linked polymer and a dermatologically acceptable carrier, characterized in that the miticidal and biocidal component is terpinen-4-ol and the cross-linked polymer is hyaluronic acid cross-linked with urea. 2. A composition according to claim 1, wherein the urea cross-linked hyaluronic acid polymer has a molecular weight ranging from 100,000 to 20,000,000 daltons, preferably 2,000,000 to 4,000,000 daltons. 3. A composition according to any one of claims 1-2, wherein the hyaluronic acid cross-linked with urea and terpinen-4-ol form a complex. 4. A complex for the prevention and / or treatment of ophthalmic and / or dermatological diseases based on hyaluronic acid cross-linked with urea and terpinen-4-ol. 5. A device comprising a solid support moistened with a composition according to any one of claims 1-3. 6. A device according to claim 5, characterized in that said solid support is made of a material selected from cotton, non-woven fabric and polyurethane, and is preferably moistened with an amount of composition ranging from 0.001 to 0.1 g / cm2. Use of a composition according to any one of claims 1-3, or a complex according to claim 4, or a device according to claim 5 or 6 to clean and / or sanitize the skin, the surface of the eye or its appendages. 8. A composition according to any one of claims 1-3, or a complex according to claim 4, for use in the prevention or treatment of ophthalmic diseases. 9. Cosmetic use of a composition according to claim 1 or 3 or complex according to claim 4, in the detersion or hygiene of the periocular area, eyelid or eyelashes. Device according to claim 5, which is a wipe, a gauze, a wipe for application in the ocular and / or periocular area. 11. A composition according to any one of claims 1-3, or complex according to claim 4, for use in the treatment of blepharitis, acute or chronic conjunctivitis, conjunctivitis with an allergic component, or in the treatment of infections of the eye caused by mites, in particular Demodex, Cheyletiella mite, or in the treatment of skin diseases, in particular caused by mites, in particular acne or rosacea.